Oral drug delivery continues to be the most popular route of administration due to its versatility, ease of administration and patient compliance. An oral medication that improves compliance, and thus results in more effective treatment, has been one of the major drivers of innovation in the oral drug delivery market.
Modified-release or a controlled-release dosage form is an advancement in the oral drug delivery which has led to improved patient compliance and reduced side effects of the drugs. “Modified-release” means that the release of the drug from the dosage form has been modified in some way with respect to an immediate-release delivery of the same drug. Usually, this is to slow the release of the drug so that the medicine doesn't have to be taken too often and therefore improves compliance. The other benefit from modifying-release is that the drug release is controlled and there are smaller peaks and troughs in blood levels, therefore reducing the chance of peak effects and increasing the likelihood of therapeutic effectiveness for longer periods of time.
Generally, controlled-release systems can be categorized into two groups based on actions. Extended-release formulations deliver a portion of the total dose shortly after ingestion and the remainder over an extended time frame. Delayed-release systems provide steady dosing after passage through the stomach. Controlled-drug delivery systems aim to maintain plasma concentration of drugs within the therapeutic window for a longer period of time, thereby to ensure sustained therapeutic action.
Further manipulation of delivery systems has led to the development of chronotherapeutic systems, where release enables a drug to take advantage of the natural biorhythms of the human body. Pulsatile drug delivery system provides a chronotherapeutic release to meet the needs of patients suffering from diseases which follow the biological rhythm, such as asthma, where episodes of attack mostly happen late at night or rheumatoid arthritis, where the pain peaks at the morning. Pulsatile drug delivery systems are characterized by at least two distinctive drug-release phases following a predetermined lag time. Drug's release may be controlled by time, by site or a combination of the two parameters.
Two of the most widely commercialized controlled-release technologies are Oros® (developed by Alza), and the Sodas® technology developed by Elan. Other successfully commercialized technologies include SkyePharma's Geomatrix®, Eurand's Diffucaps® and Elan's Codas®.
U.S. Pat. Nos. 5,318,558 and 5,221,278, assigned to Alza, claim the pulsatile delivery of agents from osmotic systems based on the technology of an expandable orifice.
U.S. Pat. No. 7,387,793, assigned to Eurand, relates to a multi-particulate pharmaceutical dosage form wherein the active drug is layered onto a neutral core (such as cellulose spheres) and then one or more rate-controlling, functional membranes are applied.
U.S. Pat. No. 6,797,283, assigned to Alza, relates to a multilayered dosage form comprising: a first layer comprising an amount of swellable polymer, said amount being sufficient to swell said first layer such that the active agent dosage form is retained within a stomach of a subject; a second layer laminated with the first layer at a common surface, said second layer comprising a therapeutic amount of an active agent and being formulated to swell to a lesser extent than the first layer; and at least one band of insoluble material circumscribing only a portion of said first layer and said second layer, said at least one band of insoluble material binding together the first layer and the second layer.
U.S. Pat. No. 6,183,778, assigned to Jagotec AG, relates to an oral dosage form in the form of a tablet, capable of providing one or more pharmaceutically active substances in two or more different releases, the dosage form comprising at least three layers of specific geometric shape, wherein the dosage form comprises:                a) a first layer from which there occurs a first release of at least one pharmaceutically active substance, wherein the release is characterized as an immediate-release or a controlled-release, the layer comprising substances which swell or solubilize when contacted with aqueous liquids;        b) a second layer from which there occurs a second release of at least one pharmaceutically active substance, wherein the at least one pharmaceutically active substance is the same as or different from the at least one pharmaceutically active substance released from the first layer in the first release, wherein the second release is characterized as a controlled-release, the second layer comprising substances that swell, or erode, or are gellable when contacted with aqueous liquids; and        c) a third layer at least partially coating one or more free surfaces of the second layer, the third layer comprising substances that swell, or erode, or are gellable when contacted with aqueous liquids, and wherein at least two layers of the dosage form are formed by the compression of a mixture of granular components.        
U.S. Pat. No. 5,783,212, assigned to Temple University of the Commonwealth System of Higher Education, discloses a multilayer tablet for release of active pharmaceutical ingredient at a constant rate with a zero order kinetic profile, in which two outer layers contain swellable and erodible polymers, an inner layer contains an active pharmaceutical ingredient and swellable and erodible polymers, and each layer differs in composition and thickness.
U.S. Pat. No. 5,626,874, assigned to Ekita Investments N.V., discloses a multilayer tablet consisting of two outer layers containing gellable or erodible polymers and an inner layer containing an active ingredient. The side surface of the inner layer occupies about 5% to 35% of the tablet's total surface.
U.S. Publication No. 2010/0040681, filed by GL Pharmtech Corp., relates to an oral sustained-release triple layer tablet, more particularly, a triple layer tablet consisting of an inner immediate-release layer containing an active pharmaceutical ingredient and two outer layers containing swellable polymers. On exposure to aqueous media, the two outer layers swell to form gelled layers surrounding the lateral side of the inner layer rapidly, thereby controlling effectively the release of drug from the inner immediate-release layer.
U.S. Pat. No. 5,549,913, assigned to Inverni Della Beffa S.p.A., discloses a multilayer tablet for release of active pharmaceutical ingredient at a constant rate with a zero order kinetic profile, in which two outer layers contain active pharmaceutical ingredient and hydrophilic polymers, and an inner layer contains a water-soluble polymer without the active pharmaceutical ingredient. The inner layer is readily dissolved in aqueous media to separate the two outer layers, and thus to increase the surface area of the matrix.
The present inventors have developed a novel multilayered coated tablet comprising at least three layers, wherein the first and third layers contain at least one active pharmaceutical ingredient and the second layer is either a placebo or an immediate-release drug layer. This tablet further comprises a delayed-release coating wherein the coating may contain one or more pore-forming agents and/or orifices on one or both sides. Further, there may be an immediate-release layer over the delayed-release coating for an initial pulse. The orifice or pore-forming agents present in the coating lead to an initial hydration and slow-release of the drug until the time it reaches the intestine. After reaching the intestine, the delayed-release coating and the second placebo or drug layer dissolve or erode separating the first and third drug layers. The first and third drug layers of the dosage form can be two extended-release layers or one immediate-release layer and another extended-release layer. The present dosage form also provides the pulsatile-release of the drug by the delivery of the drug from two or three different layers with different release rates. Further, the present dosage form can be used to formulate two incompatible drugs into a single tablet, wherein the second layer will prevent the two drugs from coming in contact with each other.